There is no stronger link between a human malignancy and a parasitic infection than the link between cholangiocarcinoma (CCA)-hepatic cancer of the bile duct epithelia-and infection with the liver fluke, Opisthorchis viverrini. O. viverrini is carcinogenic. Throughout East Asia, there is a strikingly high prevalence of CCA in regions where liver fluke infection is endemic. In particular, CCA is extremely prevalent in Northeast Thailand, where uncooked cyprinoid fish is often a dietary staple. These fish are the intermediate hosts of the liver flukes O. viverrini and Clonorchis sinensis. In Northeast Thailand and Laos, despite widespread administration of the anti-worm drug praziquantel, the prevalence of O. viverrini approaches 70% in some endemic areas. Moreover, in Thailand, liver cancer is the most prevalent of the fatal neoplasias, and rates of CCA in regions where the parasite is endemic are unprecedented-CCA is responsible for about 24% of liver cancers in the U.S.A. but represents 87% of cancers in Thailand's Khon Kaen region, the highest incidence in the world. O. viverrini infection induces inflammation of the bile ducts, resulting in DNA damage of the epithelium and subsequent malignant transformation to CCA. Among the many people infected with O. viverrini, some become heavily infected and develop CCA. The objectives of this grant application are to identify the carcinogenic molecules of O. viverrini and, because a distinct inflammation phenotype appears to predispose to CCA, to characterize the inflammation phenotype of those persons who become heavily infected with O. viverrini. Enhanced understanding of immunological and inflammation characteristics of patients with O. viverrini infections should facilitate diagnostic interventions to prevent infection and O. viverrini infection and CCA. This knowledge can be expected to guide public health policy and delivery in liver fluke endemic locations in Thailand. Moreover, characterization of the nature and action of the carcinogens of O. viverrini would be of fundamental biomedical significance.